1-thiazolin-2-yl(or thiazin-2-yl)-2-aminobenzimidazoles and derivatives thereof

ABSTRACT

THIAZOLINYL AND THIAZINYL DERIVATIVES OF 2-AMINOBENZIMIDAZOLES ARE PROVIDED HAVING THE STRUCTURE   1-(-C&lt;(-S--N=)(-R2)),2-(H2N-),(R1)N-BENZIMIDAZOLE   WHEREIN R1, R2 AND N ARE DEFINED HEREINAFTER, AND WHICH ARE USEFUL AS ANTIINFLAMMATORY AGENTS AND DISINFECTANTS AND AS INTERMEDIATES IN THE PREPARATION OF ANTHELMINTIC AGENTS.

United, States PatentOflice Patented July 23, 1974 ABSTRACT OF THE DISCLOSURE Thiazolinyl and thiazinyl derivatives of 2-aminobenzimidazoles are provided having the structure wherein R, R and n are defined hereinafter, and which are useful as antiinflammatory agents and disinfectants and as intermediates in the preparation of anthelmintic agents.

The present invention relates to thiazolinyl and thiazinyl derivatives of Z-aminobenzimidazoles having the structure wherein R is hydrogen, lower alkyl, lower alkoxy, aralkyl,

aryl, substituted aryl, acyl, aroyl, lower alkylthio, aryloxy,

arylthio, trifiuoromethyl, nitro, halogen, cyano and amino. R can be hydrogen, lower alkyl, arylalkyl, aryl or lower alkylaryl; n is l, 2, 3 or 4, preferably 1 or 2.

The radical represents a 5- or 6-membered ring containing 3 or 4 carbon atoms, respectively, wherein the additional 2 or 3 carbon atoms (not shown) may include a substituent other than hydrogen as indicated above.

The lower alkyl groups represented by the above R and R groups include straight or branched chain aliphatic hydrocarbon radicals having up to seven carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl and the like. I

The alkoxy group or that portion of the alkoxy-carbonyl group includes straight and branched chain radicals of up to and including seven carbon atoms, corresponding to the above alkyl groups, e.g., methoxy, ethoxy, propoxy, isopropoxy and the like. The aryloxy group or that portion of the aryloxy-carbonyl group includes any of the aryl groups set out below.

The term halogen includes each of the four halogens but fluorine and chlorine are preferred.

The amino groups include unsubstituted as well as monoor di-lower alkyI-, arylalkyl-, lower alkylarylor arylamino wherein lower alkyl and aryl are as defined herein, such as methyamino, ethylamino, heptylamino, dimethylamino, diethylamino, ethylmethylamino, butylinlfthylamino, ethyldipropylamino, benzylamino and the The term aryl includes monocyclic or bicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents halogen, nitro, trifiuoromethyl, alkoxy, amido or substituted amido or any of the alkyl groups mentioned hereinbefore.

The acyl and aroyl groups included herein are derived from hydrocarbon carboxylic acids of less than twelve carbon atoms, which may be exemplified by the lower alkanoic acids (e.g., formic, acetic, propionic, butyric, valeric, trimethyl acetic and caproic acids), the lower alkenoic acids (e.g., acrylic, methacrylic, crotonic, 3-butenoic and senecioic acids), the monocyclic aryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryllower alkanoic acids [e.g., phenacetic, p-phenylpropionic, a-phenylbutyric, and S-(p-methylphenyl)pentanoic acids], the cycloalkyl carboxylic acids (e.g., cyclobutane carboxylic acid, cyclopentane carboxylic acid and cyclohexane carboxylic acid), the cycloalkenyl carboxylic acids (e.g., 2-cyclobutene carboxylic acid and 3-cyclopentene carboxylic acid), the cycloalkyl and cycloalkenyl-lower alkanoic acids [e.g., cyclohexaneacetic, u-cyclopentanebutyric, 2- cyclopenteneacetic and 3-(3-cyclohexene)pentenoic acid], and the like.

Exemplary of compounds falling within the present invention include, but are not limited to, the following set out in Table A below:

2 Same as above. 1 Do. 2 Do. 2 Do. 1 Do.

3 1 Do. 1 Do.

11 N(CH3)2(6) 1 -I -I I CH3 CH1C'H (6) 1 Same as above.

14.... n 1 Same as above.

CaHsC (5) """TABLE A- Continued" R1 n Z R1 .2 n Z 15 CH5S-.(5) 1;: -1 k 'rw, 34 H 1 l I as NH1(5),. I 1 I. I, 16 1 Same as above. a. @T ,7 17L CF30 (5,6) .2 l CH3 I N CHri i Compounds of Formula I can be prepared by first converting the Z-aminobenzimidazole (II) into its salt (III) 1333;311:3331:iieriime i 3? by employing metal hydrides s h s m y'dr d P. g CF (6) ggtassium hydride and liquid ammonia, metal amides, such as sodium amide, alkali metal alkoxides, such as sodium 22 1 26 methoxide, potassium ethoxide or sodium butoxide.

--N G9 --N -H (R)n IL (a)u IL 2 2 23 O1 (5) 1 A N/ S iq H 6 I I (II) (III) CH3 H t V r v H 1 The above reaction can be brought about in -a variety 24 C3 1 (5) A of nonprotic solvents such as aromatic hydrocarbons, e.g., s N benzene, toluene or xylene, or ethers such as ethyl'ether or glyme, at temperatures ranging from about 0 to about 150 for periods of about one hour to twenty-four hours. A slight excess of the base is desirable; thus the molar 25 C2H (a) 1 ratio of Z-aminobenzimidazole II to base can range from about 1:1 to about 1:2. S N The salt (III) i reacted with an aliphatic haloalkyl- I l isothiocyanate (IV) to yield thiourea (V) which undergoes intramolecular alkylation to form the Z-aminobenz- 26 04H? (5) 1 l imidazoles (I).

s N N K J Calla-U (BL! I NH; 27 cms- 1 /I\ g s N (I V wherein X is C1 or Br and the portion 28...; (CH3)zCH(5) 1 Same as above 29 CHaO (6) 1 Do. N N 30 p 1 I (Rn v (R), I

""""""" oms N/ NH2 \N/ I S N A U s NH 115 N CHaO X J X, a1 0F: (5) 1 A \l \I s N R2 R2 U (V) 2 whichlinks N and X) in structure IV represents a chain 32 N01 (6) 1 l 0152 or 3 carbon atoms one carbon-atom of which may A include an R substituent other than hydrogen. S N n-zThe molar; ratio of 2-aminobenzimidazole (II) to halo- CH J 7 I alkylisothiocyanate (-IV) can range from 1:1. to 1:15. The-reaction time can vary from about 1 to about 24 33 .l CN (6) 1 hours at temperatures from about 25- to about 150.

ployed to form compounds of Formula I and thereafter other R radicals may be inserted in the Z-aminobenzimidazole ring in'place of one or two hydrogens, employing conventional procedures as will be apparent to one skilled in the art.

Haloalkyl isothiocyanates (IV) are readily synthesized from their corresponding haloalkyl amines (VII) and thiophos gene Bas e R2 (I Additional routes toward compounds of structure (IV) are described in Houben-Weyls Methoden Der Orga'nischen Chemie, Vol. 9,G.- Thieme Verlay Stuttgart, 1955.

Z-Aminobenzirnidazoles containing a free imino hydrogen are virtually tautom'eric systems, differing in the position of the imino hydrogen as seen below (A B). These Z-aminobe'nzimidazoles react like tautomeric mixtures of the two possible forms. The reaction products (C and D) are not necessarily obtained in equal parts but in proportions that differ from compound to compound, substituents and reaction. conditions having a pronounced eifect on the course of the reaction.

H v R- N E N N NHz R iqIl NHz I I (B) N NHz 4- R Nj NHz (c) (D) Alternatively, compounds of formula (I) can be prepared by reacting the corresponding N-thiazolinyl or N-thiazinyl-O-phenylene diamine of the structure VIII with a cyanogen halide (IX) (XCN wherein X is chlorine or bromine),

(VIII) NH2 XCN S N \I/ 32 employing a molar ratio VIII:IX within the range of from about 1:1 to about 1:5. The reaction can be carried out at temperatures ranging from 0 to about 50 for periods of about one hour to 24 hours. Solvents which can be employed include water as well as aromatic hydrocarbons such as benzene or toluene or ethers, such as ethyl ether or isopropyl ether.

' The N-thiazolinyl'or N-thiazinyl-O phenylene diami'nes starting materials VIII can be prepared as described in copending application Ser. No. 230,121 filed Feb. 28, 1972, entitled Thiazolinyl and Thiazinyl Derivatives of o-Phenylenediamines by Narayanan and Haugwitz, filed concurrently herewith; I

Examples of 2-aminobenzimidazole starting materials II which can be employed herein include the following:

TABLE B N n I N/NH2 17 5-C5H5C- Examples of N-thiazolinyl or N-thiazinyl-O-phenylene diamine starting materials VIII which can be employed herein include the following:

-NH )n R n R 1 CH3 (4, 5) 2 Same as above. 3 CI (4, 5) 2 Do. 4. l (4) 1 Do. 5.-. CHzO (4) 1 Do. 6 O2 (3) 1 Do. 7 N02 (4) 1 Do. 8 04H (4) 1 -l==N 9 Br (5) 1 -l-:I;I

CH3 10 Br (3), CHaO (5) 2 Same as above. 11 Br (5), CH3(3, 4) 3 TN SXX 12 C4Ho0 (4, 6) 2 Same as above. 13 (3, 2 Do.

. C2 5 (5),N 2(3) 2; S

, i I Cc s 15.-. -omotm (4) 1' |=N' Examples of aliphatic haloalkylisothiocyanates which can be employed herein include the following:

S CN-CH1CHgBI S CN-OHgCHgCHg Cl S CN-CHg CH-Br SCN-CH; CH--Ol The compounds of formula (I) form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate inorganic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sufate, nitrate, phosphate, oxalate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The 2-aminobenzimidazole derivatives of the invention are also useful as anti-inflammatory agents. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species, e.g., in conditions such as rheumatoid arthritis. Compounds of formula (I) may be compounded for such use according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably 100 mg. to 1 gm. per day in two to four divided doses.

The compounds of formula (I) may also be used as surface disinfectants. About 0.01 to 1 per cent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleaning agent, e.g., a solid or liquid detergent, detergent composition, for example; in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment. The compounds of formula (I) are also useful in the preparation of anthelmintic agents.

The following examples further illustrate and represent preferred embodiments of the invention:

EXAMPLE 1 2-Amino-1-(2-thiazolinyl-2-yl)benzimidazole Calcd for C H N S: C, 55.02; H, 4.51; N, 25.67 Found: C, 54.88; H, 4.63; N, 25.84

EXAMPLE 2 2-Amino-1-(5,6-dihydro-4H-1,3-thiazin-2-yl)- benzimidazole To a solution of 14.6 g. of Z-aminobenzimidazole in 350 ml. of dry glyme there is added 3.3 g. of sodium hydride and the mixture is stirred at room temperature for one hour. A solution of 19.8 g. of 3-br0mopropyl isothiocyanate in 10 ml. dry glyme is then added and the mixture is refluxed for one hour. The solvent is evaporated and water is added to the residue. The resulting solid is filtered 01f and crystallized from glyme to yield 11.0 g. of product, m.p. 174-1765".

Calcd for C H N S: C, 56.88; H, 5.20; N, 24.12 Found: C, 56.89; H, 5.36; N, 24.29

EXAMPLE 3 2-Amino-5,6-dichloro-1-(2-thiazolin-2-yl)- benzimidazole To a solution of 6.1 g. of 2-amino-5,6-dichlorobenzimidazole in ml. glyme there is added 0.9 g. sodium hydride and after one hour of stirring 3.6 g. of 2-chloroethyl isothiocyanate in 10 ml. of dry glyme. The mixture is refluxed for 1.5 hour. The solvent is evaporated under vacuum and water is added to the residue. The resulting solid is filtered off and crystallized from glyme to yield 1.9 g., m.p. 249-2525 Calcd for C H N Cl S: C, 41.82; H, 2.81; N, Found: C, 42.04; H, 2.95; N, 19.43

EXAMPLE 4 2-Amino-5 (and 6) -methyl-1-(2-thiazolin-2-y1) benzimidazole Following the procedure of Example 3 and replacing 2-amino-5,6-dichlorobenzimidazole with 2 amino 5- methylbenzimidazole the 'title compound is obtained, m.p. 210-223". I

Calcd for c n ms: c, 56.88; H,f 5.'20; N, 24.12 Y Found: C, 57.09; H, 5.47; N, 24.17

9 EXAMPLE 5 d 6) -chloro-lw-(2?thia 1i .2, 1 4 benzimidazole Following the procedure of Example} andreplacing portions 2.2 g. of cyanogen bromide. The solid changes slowly into an oil; i After l minute s there is added sodium bicarbonate .solution and the resulting solid is filtered off, crystallized from glyme-petroleum ether to yield 0.9

2-amino-5,6 dichlorobenzimidazole with 2 -=amino 5v- 5 chlorbenzimidazole the title compound is obtained, m.p. 205-225". 1 Calcd for 11 12 4 H, N, 24 12 Calcd for C H N ClS: C, 47.53; H, 3.59; N, 22.17 Found! 56.59; H, 5:30; 24-03 Found: C, 47.35; H, 3.79; N, 22.10 I 10 EXAMPLE 6 EXAMPLES 8 TO 42 2-Amino-5 (and 6) -nitro-1-(2-thiazolin-2-yl) Following the procedure of Examples 1 to 6 but subbenzimidazole stituting the Z-aminobenzimidazole derivative shown in Following the procedure of Example 3 and replacing column 1 of Table I below and the aliphatic haloal kyliso- Z-aminO-S,6-dichlorobenzimidazole with 2 amino 5- thiocyanate shown in column 2, the product shown in nitrobenzimidazole the title compound is obtained, m.p. column 3 is obtained. 228-238. Where the Z-aminobenzimidazole starting material is Calcd for C H N O S: C, 4 -60 mono-substituted and includes a substituent at the 5 or 6 Found: C, N, 26-35 20 position, then the product shown in column 3 will include EXAMPLE 7 the 6-tautomer or 5'-tautomer respectively; where the 2 Amin 1 (2 thiazo1in 5 methy1 2 y1) 2-aminobenzimidazole starting .material is monosubstib i id l tuted and includes a substituent at the 4 or 7 position,' To a Suspension of 2 of 2 aminoannin) 25 then the product shown 1n column 3 will include the methyl-Z-thiazoline in 10 ml. of water there is added in 7433mm or respectlvely- TABLE I Column 1 Column 2 Column 3 -N (Rm. J

NH: N

\NJI-NHQ H Haloalkyl lsothlocyanata a S N \i/ Example R (position) 11 (11*): (Position) I 8 (CHz)N- (5) 1 SCNCHzCH2Br (CH3)N- (5) l 9"--. 0211 0 (6) 1 SCN-CHz-CHr-Br C2H10 (6) Sameasabove.

10 04H. (7) 1 04H: (7) D0.

11 01H (5) 1 CeHu (5) D0.

12 N02 (6) 1 N02 (6) Do.

13 011 00 (6) 1 013300 (a) Do. 14 CQH5(CH2)2 (7) v 1 SON-CHz-CHr-Bl CH5 CH2 I (7) D0. 15 01H; (5) 1 SCNCHzOHz-Br 05H (5) Do.

16 H 1 SUN-CHr-CHr-B! CflHbC Do.

17 CaH CH2 (5) 1 BCN+QH2 HOHPCI CaH5CH2 (5) v 181--.; (311E500 (5) 1 SCN-CHzCHzCHr-Cl C6H5CO (5) Sameasabove 19- (12H; (5) 1 SON-QHzCHaQHr- Cl C2H5 (5) D0. 20".--" CgHgO (5 1 sow-emomcin-m 021150 (5) Do. 2 SCNCH2OH2CHzCl CH5 (5,6) Do.

1 SON-CHzGHzCHa-Bt (CzHmN (6) 5 Do. 1 SCN-CHzCHzCHz-Br 011153 (4) Do.

1 SON-CHzCHzCHz-Bt ON (6 Do.

1 SON-CHzCHzCHz-Br N05 (5) Do. 26 N02 (5) 1 SON-CHzCHzCHr-Br N02 D0.

13 I EXAMPLES 43 TO 47 the 2-(o-aminoanilino)-5-methyl-2-thiazoline with N-thiazinyl or N-thiazolinyl-o-phenylenes as shown in Column n is 1, 2, 3 or 4; wherein the term alkyl refers to alkyl groups having up to 7 carbon atoms; wherein the" term alkoxy refers to alkoxy groups having up to 7-carboriatoms; wherein the term aryl refers to phenyl or naphthyl; wherein the term monocarbocyclic aryl refers to 1 of Table II the product shown in -Column 2 is obtained:

x g TABLE II Column 2 Column 2 NH: I5 4 N t n2 y/t yi /f l i) s N \l/ S N \1/ Example R (position) 11 R (position) n R 2 CH3 (5,6) 2 Same as above. 1 N02 (5) 1 Do. 2 C 3 2 A 47 .1 (4) '1 N01 (5) 1 Same as above.

'- What is claimed is:

1. Compounds of the structur consisting of {\N and (\N iz Ra ill phenyl; and physiologically acceptable acid-addition salts thereof.

2. Compounds in accordance with Claim 1 having the structure 3. Compounds in accordance with Claim 1 having the structure "f's N structure The Ill

4. A compound in accordance with Claim 1 having the 5. A compound in accordance with Claim 1 having the 10. A compound in accordance with Claim 1 having structure the structure N c Hs -:'N ll 5 t -NH: NH I 2 N and/or its 6. A compound in accordance with Claim 1 having the II structure PC5550 tautomer. 01 N 11. A process for preparing compounds as defined in IL Claim 1 which comprises reacting a benzimidazole of the structure 01 \N/ NH:

wherein R and n are as defined in Claim 1, with a base 7. A compound in accordance with Claim 1 having the sFlected from the up consisting of metal hydrides, liquid ammonia, metal amides, and alkali metal alkoxides,

structure to form a salt of the structure 1 N N II (11 |L \N/-NH2 \N/ NH2 e s N and reacting the salt with an aliphatic haloalkyl isothiocyanate. v 1 I 12. A process for preparing a compound as defined in Claim 6 which comprises reacting a benzimidazole of the structure 8. A compound in accordance with Claim 1 having the 40 structure Cl N OzN" --}N C1 \NJI-NHI H NH:

III with a base selected from the group consisting of metal hydrides, liquid ammonia, metal amides, and alkali metal 8 N alkoxides, to form a salt of the structure C1 LNH:

and reacting the salt with 2-chloroethyl isothiocyanatet References Cited UNITED :STATES PATENTS RICHARD J. GALLAGHER, Primary Examiner u.s."c1. XR. and/or its 6-C4H9 isomer. 260-306.7, 309.2, 454, 99 9 Column Column Column Column Column Patent No 7 Dated July 23, 1974 Inventm-(S) Rudiger D. Haugwitz & Venkatachala L. Narayanan It is certified that error appears in the above-identified patent H R N (IO- and that said Letters Patent are hereby corrected as shown below:

lines 33 to 42, the formula should be labeled: I

line 49, delete complete line which reads: wherein X is C1 or Br and the portion line 62, after formulas V and VI, insert the following: wherein X is C1 or Br and the portion lines 8 to 13, the structure should be labeled:

VII

lines '30 to 36, the formulas for B should read:

III

Column 6, lines 61. to 63, Column R delete that portion which reads: SXX Column 13, Example 43, Table II, Column n, delete "H" and insert H under column R (position) Column 15, Claim 8, that portion of the last line that reads:

" N---NO should be: 6-NO Signed and sealed this 5th day of November 1974.

(SEAL) Attest:

MeCOY Ma GIBSON JR. Attesting Qfficer FORM PO-1050 (10-69) C. MARSHALL DANN Commissioner of Patents USCOMM-DC 60376-1 69 u.s. GOVERNMENT PRINTING orrlc: I," 0-356-3. 

